In our study, although patients receiving allografts preserved with UW and CS have similar short-term mortality, patients in the CS cohort have an increased incidence of RHF requiring RVAD support and a trend toward an increased need for LVAD support. Moreover, allografts preserved with UW exhibited less AIN on early post-transplant biopsies than those preserved with CS as measured by our histopathological assessment. Finally, AIN as measured by our novel scoring system is predictive of both PGD and RHF.
Numerous HPS are currently used to augment hypothermic protection during explant, transport, and implantation of cardiac allografts. In the United States, UW and CS are the most commonly utilized HPS. UW, originally designed for kidney and liver transplantation, is classified as an intracellular solution for its high potassium concentration. Theoretical benefits of high potassium concentration include rapid cardiac mechanical arrest leading to less intracellular edema and less ionic flux.3, 4
Additionally, UW contains adenosine to maintain ATP-dependent ion gradients and free radical scavengers such as lactobionate and allopurinol to mitigate ischemia-reperfusion injury.7
Moreover, several large studies have shown superior outcomes of intracellular over extracellular solutions.4, 5
However, many clinicians and researchers are reticent to use such a high potassium solution, particularly with regard to its putative but controversial effect on coronary and pulmonary vascular endothelium.2, 3, 8
Celsior, designed specifically for myocardial preservation, is classified as an extracellular solution for its relatively low potassium concentration. Theoretic benefits of CS include numerous specific additives, including mannitol, histidine, and glutathione, to mitigate ischemia-reperfusion injury, impermeants to reduce intra and extracellular swelling, glutamate to enhance energy production, a mild acidosis to prevent calcium overload, and the prevention of red blood cell aggregation.1, 7, 9, 10
However, several studies have demonstrated that more complex additives, such as glutathione, are unstable.11, 12
While both HPS contain glutathione, it is possible that CS, with its more numerous and complex additives, may not be as stable mandating optimal storage conditions of these solutions for favorable clinical outcomes.
Although there is no consensus on the optimal HPS at present, our group recently published a large registry study of almost 5,000 OHT demonstrating that patients who received an allograft preserved with UW had significantly greater short term survival than those who received an allograft preserved with CS.5
While one could speculate that this survival difference suggests that UW is a better preservative solution which more optimally supplements the effects of hypothermic storage, a large registry study precludes evaluation of preservation at the histopathological level. Therefore, we undertook the current study to better define the preservative ability of these two solutions at the cellular level.
To evaluate the impact of HPS on cardiac histopathology, we evaluated early post-transplant biopsies taking into account our previous finding of peak histologic injury occurring 16 days post-transplant.6
It is our institutional practice to obtain weekly cardiac biopsies for the first month after OHT; therefore, we evaluated the first 3 post-transplant biopsies in order to capture peak AIN. One prior study has evaluated the impact of HPS on AIN.2
However, in their study, AIN was evaluated in binary fashion. Our experience suggests that AIN is not simply a binary phenomenon. Not only can ischemia be present or absent, but there is distinct variability in the severity of necrosis. Since this variable severity of ischemia may reflect the adequacy of preservation during OHT, we created a novel yet simple grading scale for AIN. To account for the possibility of sampling error and the potential delay between ischemic insult and pathologic evidence of ischemic necrosis, we also evaluated composite scores to account for AIN as it was observed over all 3 post-transplant biopsies.
On both unadjusted and adjusted analysis, allografts preserved with UW exhibited less AIN than those preserved with CS. The decreased AIN associated with UW combined with our previous finding that UW is associated with superior survival compared to CS has persuaded us to use UW exclusively for OHT. However, we recognize that this debate is likely to continue.
To further validate our novel grading system of AIN, the impact of ischemic grade on outcomes was analyzed. When stratified by ischemic grade on the first biopsy, although there was no difference in terms of short term mortality, we believe this was due to the relatively small sample size of the four groups. However, ischemic grade as measured at the 1st biopsy was strongly predictive of PGD and the need for post-transplant LVAD and RVAD support. While it is not surprising that increased ischemic necrosis is predictive of poor allograft function, the fact that our ischemic grading system predicts poor graft function serves to validate our novel ischemic score.
There is no consensus definition of PGD after OHT. Existing definitions encompass varying degrees of inotropic or mechanical circulatory support over a widely variable duration. In an attempt to validate our score, we wanted to restrict our definition of PGD to those allografts with severe dysfunction and therefore limited our definition to include implantation of an LVAD or prolonged epinephrine support (≥10 days). Many other definitions have been proposed, pointing to the need for a consensus definition.
Our study utilizes a simple, novel schema for grading AIN. Since it is a novel system, it would require further validation in a different cohort before it could be widely applied. Our AIN scores were determined by a single cardiovascular pathologist blinded to the HPS used for preservation. This could be seen as a potential source of bias. However, the grading schema is simple and similar to currently accepted grading systems and could be reproduced at any center performing cardiac transplantation. Further research will be necessary to evaluate the generalizability of our results.
As a retrospective review, patients were not randomly assigned to HPS. Although HPS was ultimately according to surgeon preference, in general, HPS choice was time-dependent with CS utilization predominating from 2001–2008 and UW predominating before and since that time period. Despite attempts to guard against bias with multivariable analysis, we recognize this time-dependent utilization of HPS to be a potential confounder. Although we did not replicate the differential survival between HPS demonstrated in our previous research, we suspect this is due to the limited sample size of our cohort.